This study investigates the role of high mobility group AT-hook 1 (HMGA1) in chemoresistance to cisplatin (DDP) in esophageal squamous cell carcinoma (ESCC). The authors demonstrate that HMGA1 upregulates the expression of solute carrier family 7 member 11 (SLC7A11), a key transporter maintaining intracellular glutathione homeostasis and inhibiting malondialdehyde (MDA) accumulation, thereby suppressing ferroptosis. HMGA1 acts as a chromatin remodeling factor, promoting the binding of activating transcription factor 4 (ATF4) to the promoter of SLC7A11, enhancing its transcription and maintaining redox balance. Depletion of HMGA1 enhances the sensitivity of ESCC to ferroptosis, as evidenced by increased cell death and decreased cell viability. In vivo experiments using syngeneic allograft tumor models and genetically engineered mice further validate that HMGA1 depletion promotes ferroptosis and restores the sensitivity of ESCC to DDP, enhancing therapeutic efficacy. These findings highlight HMGA1 as a critical driver of DDP resistance in ESCC and suggest HMGA1-based strategies as potential approaches to overcome chemoresistance.This study investigates the role of high mobility group AT-hook 1 (HMGA1) in chemoresistance to cisplatin (DDP) in esophageal squamous cell carcinoma (ESCC). The authors demonstrate that HMGA1 upregulates the expression of solute carrier family 7 member 11 (SLC7A11), a key transporter maintaining intracellular glutathione homeostasis and inhibiting malondialdehyde (MDA) accumulation, thereby suppressing ferroptosis. HMGA1 acts as a chromatin remodeling factor, promoting the binding of activating transcription factor 4 (ATF4) to the promoter of SLC7A11, enhancing its transcription and maintaining redox balance. Depletion of HMGA1 enhances the sensitivity of ESCC to ferroptosis, as evidenced by increased cell death and decreased cell viability. In vivo experiments using syngeneic allograft tumor models and genetically engineered mice further validate that HMGA1 depletion promotes ferroptosis and restores the sensitivity of ESCC to DDP, enhancing therapeutic efficacy. These findings highlight HMGA1 as a critical driver of DDP resistance in ESCC and suggest HMGA1-based strategies as potential approaches to overcome chemoresistance.